POS0857 PHARMACOKINETICS, SAFETY, AND EFFICACY OF SUBCUTANEOUS BRODALUMAB FOR SYSTEMIC SCLEROSIS WITH MODERATE-TO-SEVERE SKIN THICKENING: A SINGLE-ARM, OPEN-LABEL, MULTI-DOSE, PHASE 1 TRIAL
Authors: T. Fukasawa, A. Yoshizaki, H. Kagebayashi, S. Sato
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic sclerosis (SSc) is a rare autoimmune disease that causes fibrosis of the skin and internal organs. The mechanism of SSc pathogenesis and progression is not clear yet and SSc is therefore a disease with high unmet medical need. Though recent evidence reveals that interleukin-17 (IL-17) may play an essential role in the pathogenesis of multiple autoimmune inflammatory diseases, the role of IL-17 in SSc has not been established. Objectives This trial assessed the pharmacokinetics (PK), safety, and efficacy of multiple subcutaneous doses of brodalumab, a fully human anti–IL-17RA monoclonal antibody that inhibits the activity of IL-17A, IL-17C, IL-17F, IL-17A/F, and IL-17E (also called IL 25), in Japanese SSc patients with moderate-to-severe skin thickening. Methods In this trial, eligible patients (the modified Rodnan skin score (mRSS):10-29, present with the first symptoms of SSc other than Raynaud’s phenomenon within 60 months at enrolment) were enrolled and received subcutaneous brodalumab 210 mg every 2 weeks (Q2W) during the 52-week period. Primary endpoints were PK and safety. Secondary endpoints included change from baseline in mRSS and Composite Response Index in SSc (CRISS) score. Exploratory endpoints included lymphocyte subset testing. Results Eligible 8 patients were enrolled. Mean (SD) age was 53.6 (10.6) years. All patients had diffuse cutaneous SSc, total mRSS was 23.1 (5.1) and disease duration was 2.2 (1.9) years. Mean (SD) serum brodalumab trough concentration increased to 21.8 (16.7) μg/mL at week 2 and remained almost constant at week 52. Drug-related treatment-emergent adverse events were observed in three patients: oral candidiasis (n=3), vulvovaginal candidiasis (n=1), and arthralgia (n=1). A rapid decrease in mRSS was observed as early as week 4 (-1.3 vs baseline, p&lt;0.005), which continued until week 52 (-10.125 vs baseline, p&lt;0.0001). Brodalumab reduced dermal thickness of the lesional skin consistent with the decrease in mRSS. All patients achieved a CRISS score ≥0.6 at week 24, which continued until week 52. Brodalumab induced Th17/Treg balance to Treg dominance over 52 weeks (vs baseline, p&lt;0.05). The rapid decrease in the number of immunoglobulin G class-switched memory B cells and plasmablasts (vs baseline, p&lt;0.01) was accompanied by an increase in the number of transitional B cells (vs baseline, p&lt;0.05) by week 52. Conclusion Brodalumab demonstrated a rapid and sustained decrease in mRSS over 52 weeks in Japanese SSc patients with moderate-to-severe skin thickening, which could be attributed to its direct effects on fibroblasts and indirect effects via impacts on B and T cell subsets. References None. Mean Change from Baseline in mRSS and Mean mRSS over the 52-week follow up. (Mean +/- SD) Table 1. Other efficacy endpoints Baseline Week 12 Week 24 Week 52 Number of finger digital ulcers mean 1.9 1.6 1 0.3 SD 2.3 2.3 1.6 0.7 P value NA 0.17 0.04 0.04 Percent predicted FVC, % mean 86.7 87.1 85.9 85.3 SD 13.1 14.4 14 14.1 P value NA 0.7 0.45 0.3 Percent predicted DLCO, % mean 92.6 89.3 88.9 89.1 SD 22.5 22.9 19.4 22.2 P value NA 0.06 0.09 0.18 PGA, mm mean 48.6 47.9 43.4 45.8 SD 23.9 25.7 26 24.6 P value NA 0.66 0.04 0.71 CGA, mm mean 68.9 53.5 39.5 30.3 SD 23.9 19 16.7 13.9 P value NA &lt;.001 &lt;.001 &lt;.001 J-HAQ-DI score mean 0.22 0.17 0.13 0.19 SD 0.49 0.44 0.35 0.35 P value NA 0.4 0.17 0.7 Acknowledgements We gratefully acknowledge the patients and their families for their participation in this trial. We thank all the investigators who had a part in this study for their contribution. Disclosure of Interests Takemichi Fukasawa: None declared, Ayumi Yoshizaki: None declared, Hisashi Kagebayashi Employee of: Kyowa Kirin Co., Ltd., Shinichi Sato Consultant of: Kyowa Kirin Co., Ltd.